Project Summary This application titled ?Small Molecule Neurotrophin Receptor Ligands to Treat Alzheimer?s Disease? is in response to NIH Drug Discovery for Nervous System Disorders (R21; PAR-16-042). We will determine if small molecule ligands targeted to the TrkB and TrkC neurotrophin (NT) receptors will inhibit fundamental pathophysiological mechanisms underlying AD. In AD, multiple processes including aging, accumulation of amyloid and pathological forms of tau, and inflammation lead to synaptic dysfunction, decreased dendritic spines, and the eventual loss of synapses and neurons. NTs, including brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT3), are protein ligands essential for the maintenance and function of neuronal synapses. BDNF and NT3 bind to TrkB and TrkC, respectively, to trigger intracellular signaling pathways that are highly integrated with, and hence situated to oppose, the degenerative signaling in AD. Furthermore, disrupted NT signaling contributes to the development of AD neuropathology and memory deficits. We hypothesize that therapeutically restoring or augmenting TrkB and/or TrkC signaling will counteract neurodegenerative signaling in AD thereby inhibiting hallmark AD pathologies. Our laboratory developed small molecule NT receptor ligands that bind to and activate TrkB or TrkB and TrkC. Previous published studies with the TrkB ligand showed that it entered the brain and was neuroprotective in numerous mouse models of neurodegenerative disorders. Our preliminary results with the TrkB/TrkC ligand showed that it reduced tau pathology, decreased dendritic spine loss, and improved cognition in the A?PPL/S mouse model of AD. These results established small molecule TrkB/C ligands as candidate AD therapeutics. While brain levels of the ligands were sufficient to produce neuroprotective effects when given systemically, favorable brain levels after oral delivery are necessary for drug development. To this end, we developed novel derivatives of these ligands that enter the brain more readily producing higher brain concentrations than the original ligands and have neurotrophic effects similar to that of BDNF. Thus, the proposed research aims to determine if these newly derived small molecule TrkB and TrkB/TrkC ligands will activate their intended receptors and initiate downstream signaling in a dose-dependent manner and prevent memory deficits and psychological disturbances as well as neuropathology in the A?PPL/S mouse model of AD. Targeting TrkB together with TrkC is a novel therapeutic strategy for AD, and, to our knowledge, our laboratory is the only source of a small molecule TrkB/TrkC ligand capable of testing the efficacy of simultaneously targeting these two NT receptors. This approach has the potential for synergistic intracellular signaling, as can occur with Trk receptors, and combatting multi-faceted pathological mechanisms seen in AD.